DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children’s Oncology Group and the Childhood Cancer Survivor Study

Wang X, Singh P, Cejas RB, Zhou L, Sharafeldin N, Trainor PJ, Landier W, Cheng C, Hageman L, Wang F, Sapkota Y, Yasui Y, Hudson MM, Chow EJ, Armenian SH, Neglia JP, Hawkins DS, Ginsberg JP, Burridge PW, Armstrong GT, Bhatia S. DNA Damage Response and Repair Genes and Anthracycline-Induced Cardiomyopathy in Childhood Cancer Survivors: A Report From the Children’s Oncology Group and the Childhood Cancer Survivor Study. Circ Genom Precis Med. 2025 Apr;18(2):e004813. doi: 10.1161/CIRCGEN.124.004813. Epub 2025 Mar 28. PMID: 40151933; PMCID: PMC11999796.

Anthracyclines induce cardiotoxicity via DNA double-strand breaks (DSBs) and reactive oxygen species (ROS) formation, resulting in cardiomyocyte dysfunction. The role of DNA damage response/repair (DDR) genes in anthracycline-induced cardiomyopathy remains unstudied. We conducted a gene-based and pathway-based analysis to examine main-effect and gene-anthracycline interaction effect between DDR genes and anthracycline-induced cardiomyopathy. A discovery analysis performed with a matched case-control set of anthracycline-exposed non-Hispanic White childhood cancer survivors from COG-ALTE03N1 (113 cases; 226 controls) was replicated using a cohort of anthracycline-exposed non-Hispanic White childhood cancer survivors from the Childhood Cancer Survivor Study cohort (n=1,658; 97 cases). Functional analyses were performed by examining response to doxorubicin of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) with CRISPR/Cas9-mediated knockout of prioritized genes.